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Endocrine Control of Growth. Endocrine glands. Pituitary. A nterior pituitary - oral ectoderm. P osterior pituitary - neuroectoderm . Hypothalamic hormones are secreted to the anterior lobe by way of a special capillary system, called the hypothalamic- hypophysial portal system
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Pituitary • Anterior pituitary - oral ectoderm. • Posterior pituitary - neuroectoderm. Hypothalamic hormones are secreted to the anterior lobe by way of a special capillary system, called the hypothalamic-hypophysial portal system The anterior pituitary synthesizes and secretes: • Growth hormone ('HGH' or 'GH' or somatotropin), released under influence of hypothalamic Growth Hormone-Releasing Factor (GHRF), inhibited by hypothalamic somatostatin • Thyroid-stimulating hormone (TSH), released under influence of hypothalamic Thyrotropin-releasing Factor (TRF); inhibited by somatostatin
Pituitary • Adrenocorticotropic hormone (ACTH), released under influence of hypothalamic Corticotropin-Releasing Factor (CRF) • Gonadotropins • Luteinizing hormone (also referred to as 'Lutropin' or 'LH'). • Follicle-stimulating hormone (FSH), both released under influence of Gonadotropin-Releasing Hormone (GnRH)
Insulin-like Growth Factor System • 3 ligands • IGF-1 = Somatomedin-C • IGF-2 • Insulin • 6 binding proteins • IGFBP-1 to -6 • Cell surface receptors that mediate the ligand action
Growth Hormone • Pulsatile secretion from anterior pituitary; maximum during early stages of deep sleep • Increases DNA synthesis and cell multiplication • Adequate levels of thyroid hormone required:"permissive"
HGH Adipose Tissue ↓Glucose Uptake ↑Lipolysis ↓Adiposity Liver ↑RNA Synthesis ↑Protein Synthesis ↑Gluconeogenesis ↑IGF-1 Muscle ↓Glucose Uptake ↑Amino Acid Uptake ↑Protein Synthesis ↑Lean Body Mass IGF-1 Local production Bone, Heart, Lungs etc ↑Amino Acid Uptake ↑Protein Synthesis ↑RNA Synthesis ↑DNA Synthesis Organ Size Organ Function Chondrocytes ↑Amino Acid Uptake ↑Protein Synthesis ↑RNA Synthesis ↑DNA Synthesis ↑Collagen ↑Chondroitin Sulphate ↑Cell Size and Number ↑Linear Growth
GH & IGF Interactions in Long Bone Growth Stimulates proliferation of chondrocyte precursors and thus expands the proliferative chondrocyte pool and the hepatic and/or local production of IGF-1 Germinal Zone GH IGF-2 Proliferative Zone IGF-2 IGF-2 IGF-2 Stimulates clonal expansion by autocrine/paracrine mechanisms Promotes chondrocyte hypertrophy Hypertrophic Zone IGF-1
Hypopituitarism • 16 year old boy with hypopituitarism due to craniopharyngioma • Height = 137 cm
Acromegaly Greek akros "extreme" or "extremities" and megalos "large"
Jaws – James Bond Movie • Richard Kiel • 7’ 1.5” • The Spy Who Loved Me, 1977
Thyroid • 3–4 weeks of gestation, the thyroid gland appears as an epithelial proliferation in the floor of the pharynx at the base of the tongue • Over the next few weeks, it migrates to the base of the neck, passing anterior to the hyoid bone.
Thyroid • Thyrotropin-releasing factor (TRF) and thyroid-stimulating hormone (TSH) start being secreted from the fetal hypothalamus and pituitary at 18-20 weeks of gestation • Fetal production of thyroxine (T4) reach a clinically significant level at 18–20 weeks. • Fetal triiodothyronine (T3) remains low until 30 weeks of gestation • Fetal thyroid hormones tend to protect the fetus against brain development abnormalities caused by maternal hypothyroidism.
Goiter “Derbyshire neck”
Thyroid Hormones • TSH (Thyrotropin) from Ant. Pituitary stimulates production of Thyroxine • Tri-iodothyronine is mainly produced in target peripheral tissues from Thyroxine • Tri-iodothyronine is more potent and rapidly acting being calorigenic (stimulate oxygen uptake and energy expenditure)
Thyroid Hormones • Essential for RNA synthesis • Increase in metabolic rate • Increased thyroxine causes: • weight reduction; • increased heart rate and force of contraction; • increased nervous system activity
Thyroid Hormones • Cretins seldom appear hypothyrotic until several weeks after birth but do have retarded bone growth at birth • They can have irreparable brain damage although therapy was started within 1 or 2 months
8 day old twins • most athyrotic children are born with normal size but retarded bone development • Athyrotic (left) • 3.5 kg, 53cm • Euthyrotic (right) • 2.9 kg, 50cm
Hyperthyroidism • Graves’ disease • Autoimmune disease • Exopthalmus “bug-eyes” • High metabolic Rate • Early death from heart attacks Marty Feldman -”bug-eyed” British comedian • Died at 39 of a heart attack • Video– Young Frankenstein
Parathyroids - Parathormone • Essential for regulation of calcium and phosphate metabolism • Particularly important for normal bone and tooth development • Maintains stable plasma calcium concentrations by stimulating osteoclastic activity • Thyrocalcitonin (from thyroid) has opposite effects
INSULIN • CARBOHYDRATES • used preferentially and excess is stored as fat • ABSENCE OF INSULIN • Fatty acids are mobilized and utilized in place of carbohydrates
Potent effects of Insulinon Protein Metabolism • Increased rate of transport of amino acids through cell membrane • Increased formation of RNA • Increased formation of protein by ribosomes
Complex Interaction between GH and Insulin ↑ HGH ↑ Protein Synthesis ↑ Growth Protein Intake ↓↑Caloric Storage ↑ IGF-1 ↑ Insulin
↓ HGH ↓↑ Protein Synthesis ↓↑Growth Carbohydrate Intake ↑Caloric Storage ↓↑IGF-1 ↑ Insulin
↑ HGH ↓ Protein Synthesis ↓ Growth Fasting ↑Caloric Mobilization ↓ IGF-1 ↓ Insulin
Insulin Imbalance Insulin Deficiency • Can retard growth nearly as much as GH deficiency Hyperinsulinism • Can result in accelerated growth • (but also accelerated maturity rate)
Gonadal Growth • The size and structure of the gonads does not change much prior to puberty.
Gonadal Hormones • Both sexes: Androgens & estrogens (adrenals) in small, constant levels in the urine • Gonadotrophins from Ant. pituitary stimulate development and function of the gonads • Androgens and Estrogens also produced by Adrenals. • Increased production at puberty.
Biological Activity of Androgens • Relative influence of gonadal or adrenal sources unknown. • Testicular androgens have greater biological activity than adrenal androgens • Young castrates: Adrenals not able to compensate for lost testicular production • IN FEMALES: After puberty most androgenic effects are produced by the adrenals • Majority of testosterone produce in the liver • IN MALES: Testes secrete estrogens
Sexual Development • Males and females follow the same pattern of growth to 6 weeks of gestation • At 12 weeks sex can be determined by external appearance
Sexual Development • Removal of gonads leads to female development • Local application of high concentrations of androgens causes: • development of Wolffian elements; no effect on mullerian elements • Destruction of one testis can lead to: • normal male development on unaffected side mullerian structures developing on affected side
Testosterone • FSH (ICSH (ant. pit.)) causes release of testosterone • Androgens are also produced by the testes
Metabolic action of Testosterone • Protein anabolism dependent on critical level of insulin • increased protein formation • increased cholesterol, triglycerides and F.F.A. production • decrease in phospholipids • increased retention of sodium, chlorides & potassium • increased muscular development
Metabolic action of Testosterone • Increased rate of skeletal maturation and closure of epiphyses. • closure of epiphyses more affected than linear growth • greater effect closer to puberty • facial development • Spermatogenesis complete 2 to 3 years after puberty.